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Synthesis and Dopamine Transporter Affinity of 2-(Methoxycarbonyl)-9-methyl-3-phenyl-9-azabicyclo[3.3.1]nonane Derivatives

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journal contribution
posted on 22.11.1996, 00:00 by Zhengming Chen, Sari Izenwasser, Jonathan L. Katz, Naijue Zhu, Cheryl L. Klein, Mark L. Trudell
A series of 9-methyl-3β-phenyl-2-substituted-9-azabicyclo[3.3.1]nonane derivatives were synthesized and evaluated as cocaine-binding site ligands at the dopamine transporter (DAT). The conformation of the bicyclic structures and the stereochemistry of the substituents were determined by NMR and X-ray crystallography. The in vitro binding affinity (Ki) of the 9-azabicyclo[3.3.1]nonane derivatives was measured in rat caudate-putamen tissue, and they were found to be 100-fold (Ki = 2−14 μM) less potent than cocaine and other tropane analogs. From these results it is evident that the cocaine-binding site at the DAT is very sensitive to structural modifications of the unsubstituted methylene bridge [C(6)−C(7)] of cocaine and cocaine-like compounds.